PROJECT SUMMARY/ABSTRACT Kaposi sarcoma (KS) has become one of the most common malignancies in sub-Saharan Africa in adults and children alike. Linked to the particularly high prevalence of Kaposi sarcoma herpesvirus (KSHV) infection in the region, early reports of endemic KS from fifty years ago have been recently overshadowed by the massive increase in KS incidence coinciding with the HIV epidemic in Africa. Very little has been established about the clinical and biological distinctions between HIV-related and endemic HIV-unrelated pediatric KS. Comparing the dramatically different experiences with KS in the United States/Europe with those in Africa (in both adults and children), one must consider the hypothesis that distinct virologic characteristics of endemic KSHV infection in Africa contribute to the divergence in clinical observations between regions. With increased efforts to deliver combination antiretroviral therapy (cART) to the millions of HIV- infected children in Africa over the past decade, pediatric KS has surfaced as an important public health issue. As one of the most common childhood cancers in many regions of Africa, KS has become the second most common pediatric malignancy in Malawi after Burkitt lymphoma. Although early observations reported high mortality rates in pediatric KS despite the availability of cART, the survival rate for children with KS has recently increased to nearly 60% due to increased awareness of the unique clinical features of pediatric KS combined with improved infrastructure, increased access to diagnostic, therapeutic and supportive care resources, and continued dedication to providing sustainable mechanisms for lifelong cART. As one of the most common childhood malignancies, and one with a readily identifiable causative agent in KSHV, increasing the focus on the pathophysiologic pathways in pediatric KS represents an incredible opportunity to improve long-term outcomes for large numbers of patients. Very little is known about the biological underpinnings of pediatric KS, yet its unique clinical characteristics must certainly have biological links that may not only inform treatment strategies for patients, but our overall insight into molecular mechanisms of KSHV oncogenesis. Therefore, the goal of this proposal is to examine the distinctions in the transcription profile of KSHV in children and adolescents with HIV-related KS compared to HIV-negative patients with endemic KS in Malawi, a KSHV-endemic region of Africa with high HIV prevalence. Our hypothesis is that distinct biological mechanisms drive different pathologies and treatment-response patterns in HIV-related KS compared to HIV-negative endemic KS. This proposal aims to evaluate the KSHV transcription profile of HIV-negative endemic and HIV-related pediatric KS patients obtained from two cohorts?(1) a retrospective cross-sectional cohort utilizing existing specimens, and (2) a prospective longitudinal cohort. Associations between virologic characteristics (KSHV transcription profile patterns, KSHV viral load, and interleukin-6 levels) and clinical characteristics including treatment outcomes will also be examined. Ultimately, this proposal seeks to determine the unique features of KSHV virology and how they influence the distinctions between clinical variants of pediatric KS. This information may enlighten new pathways for treating KS, KSHV, and other associated malignancies and ultimately improve long-term outcomes for patients worldwide.